Diagnostic evolution of carbonic anhydrase 3 (CA3) in Amyotrophic Lateral Sclerosis (ALS): an emerging prognostic biomarker

INTRODUCTION: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease traditionally viewed as a motor neuron disorder in which muscle atrophy occurs secondary to neuronal loss. However, recent clinical proteomic advances have highlighted carbonic anhydrase 3 (CA3), a muscle-enriched enzyme, as a promising biomarker associated with ALS disease progression. Therefore, considering ALS a neurocentric disease is not untenable. AREAS COVERED: In this review, the authors examined the emergence of CA3 as an ALS biomarker and evaluated evidence from recent large-scale clinical consortium studies supporting its diagnostic and prognostic utility. They also compare CA3 with established biomarkers, neurofilament light chain (NEFL), a surrogate endpoint approved by the FDA. EXPERT OPINION: Discoveries of CA3 biomarker in ALS highlight that peripheral skeletal muscle is not merely a passive bystander, but an integral participant in ALS disease progression. Unlike NEFL, which primarily reflects neuroaxonal injury, CA3 may capture early neuromuscular dysfunction preceding motor neuron degeneration. CA3's emergence as an ALS biomarker supports a more integrated neuromuscular model of ALS and provides a compelling rationale for incorporating CA3 into multimodal diagnostic, prognostic, and pharmacodynamic biomarker panels to accelerate ALS drug discovery, therapeutic evaluation, and precision clinical trial development, highlighting their complementary roles in early diagnosis, patient stratification, and therapeutic clinical trial design.